DE4337416A1 - 10,11beta-C¶2¶-bridged steroids - Google Patents

Description

The present invention relates to 10,11β-C₂-bridged steroids of the general formula I.

wherein
R¹ and R² each for a hydrogen atom, together for an additional bond or together for an α-methylene group,
R³ for one oxygen atom, the hydroxyimino group or two hydrogen atoms,
R⁶ for a hydrogen, fluorine, chlorine or bromine atom or for an α- or β-C₁-C₄-alkyl radical when R ^{6 '} and R⁷ represent hydrogen atoms, or else
R⁶ for a hydrogen, fluorine, chlorine or bromine atom or for a C₁-C₄-alkyl radical if R⁶ ^′ and R⁷ together represent an additional bond,
R⁷ for an α- or ß-standing C₁-C₄-alkyl radical when R⁶ and R⁶ ^' represent hydrogen atoms, or else
R⁶ and R⁷ together for an α- or ß-permanent methylene group and R⁶ ^' , for a hydrogen atom or
R⁶ and R ^{6 ′} together for an ethylene group or methylene group and R⁷ for a hydrogen atom,
R¹³ represents a methyl or ethyl group,
R¹⁴, R¹⁵ and R¹⁶ each represent a hydrogen atom or
R¹⁴ for a hydrogen atom and R¹⁵ and R¹⁶ together for an additional bond or an α- or ß-methylene group, or
R¹⁶ for a hydrogen atom and R¹⁴ and R¹⁵ together for an additional bond,
R¹⁷ ^β for a hydroxy, C₁-C₄ alkoxy or C₁-C₄ alkanoyloxy group and
R¹⁷ ^α for a hydrogen atom, for a radical - (CH₂) _n CH₂Z, where n = 0, 1, 2 or 3 and Z is a hydrogen atom, the cyano group, a radical CO₂R¹⁸ with R¹⁸ in the meaning of a C₁-C₄ alkyl group or a Radical OR¹⁹ with R¹⁹ is hydrogen, a C1-C4-alkyl or C1-C4-alkanoyl group,
for a grouping - (CH₂) _m C≡CY, where m = 0, 1 or 2 and Y is a hydrogen atom, a C₁-C₄-alkyl or a C₁-C₄-hydroxyalkyl radical or a fluorine, chlorine, bromine or Is iodine atom for a grouping -CH = C = CR²⁰R²¹, where R²⁰ and R²¹ independently of one another represent a hydrogen atom or a C₁-C₄-alkyl group, or
R¹⁷ ^β for a C₁-C₄ alkanoyl group and R¹⁷ ^α for a hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkanoyloxy or C₁-C₄ alkyl group, or
R¹⁶ and R¹⁷ ^α together for an α-methylene group, or
R¹⁷ ^α and R¹⁷ ^β together for a radical of the formula

with x = 1 or 2
stand.

The C₁-C₄ alkyl groups mentioned above as possible substituents can be a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or tert. -Butyl group act, preferably around a methyl group.

As C₁-C₄ alkoxy groups come the corresponding alkyl groups mentioned above Alkoxy groups in question, with a methoxy group being preferred.

Possible C₁-C₄-hydroxyalkyl groups are the simply hydroxylated alkyl radicals of the above explicitly named alkyl groups; the hydroxyl group is preferably on terminal carbon atom of the alkyl group.

For the possible C₁-C₄ alkanoyl groups, a formyl, acetyl, propionyl, butyryl or isobutyryl group; primarily this is an acetyl group. As C₁-C₄- Alkanoyloxy groups are the formyloxy, acetoxy, propionyloxy, butyryloxy or Isobutyryloxy group possible; an acetoxy group is preferred.

According to the present invention, preference is given to those compounds of the general formula I in which
R³ for one oxygen atom or two hydrogen atoms
R⁶ and R ^{6 '} each for a hydrogen atom or for a three ring formed together with the carbon atom 6, or
R⁶ for a chlorine or bromine atom or for a straight-chain saturated α- or ß-position C₁-C₄-alkyl radical, or
R ^{6 '} and R⁷ together for a ß-standing methylene bridge or together for an additional double bond, or
R⁷ represents a straight-chain or branched-chain saturated α- or ß-standing alkyl radical with up to 4 carbon atoms,
R¹⁴, R¹⁵ and R¹⁶ each represent a hydrogen atom or
R¹⁴ for an α-hydrogen atom and R¹⁵ and R¹⁶ together for an additional bond or for a β-methylene bridge, and

mean,
and the other substituents can all have the meanings given in formula I.

The compounds mentioned below are particularly preferred according to the invention:
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-en-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-ene-3,20-dione;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregna-4,6-diene-3,20-ion;
17- (acetyloxy) -6α-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-ene-3,20-dione;
17- (acetyloxy) -6-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregna-4,6-diene-3,20-ion;
17- (acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 19-norpregn-4-en-3 , 20-dione;
17- (acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 19-norpregna-4,6-diene -3,20-dione;
17- (acetyloxy) -6-methyl-1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyelo propa [1,2] -19-norpregna- 4,6-diene-3,20-dione;
17- (Acetyloxy) -6-chloro-1ß, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 19-norpregna-4 , 6-diene-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregn-4-ene-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregn-4-en-3,20-dione;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo- 19-norpregn-4-en-3,20-dione;
17- (acetyloxy) -6-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo- 19-norpregna-4,6-diene-3,20-dione;
17- (Acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10, 9,11] [3′′H] cyclopropa [1,2] - 18a-homo-19-norpregn-4 -en-3,20-dione;
17- (acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 18a-homo-19-norpregna-4 , 6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-1β, 2β, 4 ′, 5 ′, 9, 11α-hexahydrocyclopenta [10,9,11] [3′′H] cyelopropa [1,2] - 18a-homo-19 -norpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 18a-homo-19 -norpregna-4,6-diene-3,20-dione;
3 ′ ′, 16β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] cyclopropa [16,17] -19-norpregn- 4-en-3,20-dione;
3 ′ ′, 16β, 4 ′, 5 ′, 9,11α-hexahydroeyclopenta [10,9,11] cyclopropa [16,17] -18a-homo- 19-norpregn-4-en-3,20-dione;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one;
17β-hydroxy-17α- (propa-1,2-dienyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en- 3-one;
3 ′ ′, 4 ′ ′, 4 ′, 5 ′, 9,11α- [hexahydrocyclopent [10,9,11] estr-4-en-17β, 2 ′ ′ (5 ′ ′) -furan] -3,5 ′ ′ -Dion;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestr-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo estr-4-en-3-one;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-4,15-dien-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] -estra-4,15-dien-3-one;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestra-4,15-dien-3-one;
17β-Hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestra- 4,15-dien-3-one.

19,11β-bridged steroids emerge from DE-A 37 08 942 (EP-A 0 283 428). Both Known compounds are the two carbon atoms 11 and 19 by two neighboring ones Bridges carbon atoms of a generally substituted phenyl ring. Both the known as well as the compounds described here are characterized by an extraordinary high affinity for the gestagen receptor.

In the gestagen receptor binding test for gestagen effects using cytosol Rabbit uterine homogenate and ³H-progesterone as reference substance show the new ver bindings have a very strong affinity for the gestagen receptor.

While this strong bond in the known compounds, however, primarily too characterized competitive progesterone-antagonistic activity and leads these compounds thus especially for triggering abortions, against hormonal irregularities, for men structural triggering and can be used for induction of labor, the Compounds according to the invention by strong agonistic, d. H. gestagen effectiveness.

The compounds of general formula I also show effects on others Steroid receptors.

Because of their high gestagenic activity, the new compounds of the general Formula I used alone or in combination with estrogens in contraceptive preparations become.

The dosage of the compounds according to the invention in contraceptive preparations should be preferred wise be 0.01 to 2 mg per day.

The gestagenic and estrogenic active ingredient components are in contraceptive preparations preferably administered orally together. The daily dose is preferably administered once follows.

Preferred estrogens are synthetic estrogens such as ethinyl estradiol, 14α, 17α-ethano-1,3,5 (10) -estratrien-3,17β-diol (WO 88/01275) or 14α, 17α-ethano- 1,3,5 (10) -estratrien-3,16α, 17β-triol (WO 91/08219) into consideration.  

The estrogen is administered in an amount equal to that of 0.01 to 0.05 mg of ethinyl estradiol corresponds.

The new compounds of general formula I can also be used in preparations for treatment gynecological disorders and substitution therapy. Because of her Compounds with a favorable activity profile are particularly suitable for the treatment of premenstrual complaints, such as headaches, depressive mood mungs, water retention and mastodynia. Premium the daily dose during treatment Current complaints are around 1 to 20 mg.

The formulation of the pharmaceutical preparations based on the new compounds takes place in in a manner known per se by adding the active ingredient, optionally in combination with a Estrogen, with the carrier substances, diluents, commonly used in galenics, if necessary, flavor corrections etc., processed and in the desired application transferred form.

For the preferred oral application, tablets, coated tablets, capsules, pills, Suspensions or solutions in question.

Oily solutions, such as solutions, are particularly suitable for partial application in sesame oil, castor oil and cottonseed oil. Can increase solubility Solubilizers, such as benzyl benzoate or benzyl alcohol, can be added.

The compounds of general formula I can also be administered continuously by an intrauterine Release system (IUD) can be applied; the release rate of the active compound (s) is chosen so that the daily released dose within the already specified Dosage ranges.

It is also possible to incorporate the substances according to the invention into a transdermal system work and apply them transdermally.

Finally, the new compounds can also be used as a gestagen component in the recently known compositions for female fertility control, which are characterized by feature the additional use of a competitive progesterone antagonist to (H.B. Croxatto and A.M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. By Runnebaum, Rabe & Kiesel - Vol. 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group - 1991, page 245).  

The dosage is in the range already specified, the formulation can be as with konven tional OC preparations. The application of the additional, competitive progesterone Antagonists can also be carried out sequentially.

The intermediate compounds for obtaining the new compounds of the general formula I are prepared according to the invention as illustrated in the scheme below.

The interconnections 6, 7, 8, 11 and 12, summarized as connections of general formulas IIa and IIb also belong to the subject of the present Invention:

IIa: A and B each represent a hydrogen atom or together an additional bond
and
K¹⁷ represents a free or protected in the form of a ketal keto oxygen atom;
IIb: K³ stands for a keto oxygen atom protected in the form of a ketal;
R in both cases represents a methyl or ethyl group and K³ and K¹⁷ preferably mean a 1,2-ethanediylbis (oxy) or also a 2,2-dimethyl-1,3-propanediylbis (oxy) protective group.

The following intermediate compounds of the general formulas IIa and IIb are preferred according to the invention:
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-1,4-dien-3-one;
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one;
3,3- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-5-en-17-one;
4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-1,4-diene-3,17-dione;
4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3,17-dione;
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-estra -1,4-dien-3-one;
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestr -4-en-3-one;
3,3- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestr- 5-en-17-one;
4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestra-1,4-diene-3,17-dione;
4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestr-4-en-3,17-dione.

Representation of the basic structure

Variant I

R = methyl, ethyl;
Instead of the 1,2-ethanediylbis (oxy) protecting group on the oxygen atom of carbon atom 17, other keto protecting groups such as, for example, the 2,2-dimethyl-1,3-propanediylbis (oxy) group are also suitable according to the invention.

Instead of the 1,2-ethanediylbis (oxy) protective group on the 3-keto oxygen atom, there are also others Keto protecting groups such as the 2,2-dimethyl-1,3-propanediylbis (oxy) group suitable according to the invention.  

Variant II

R = methyl, ethyl;

Instead of the 1,2-ethanediylbis (oxy) protecting group on the oxygen atom of carbon atom 17 there are also other keto protective groups in compound 6 such as the 2,2-dimethyl 1,3-propanediylbis (oxy) group suitable according to the invention.  

Variant III

R = methyl, ethyl;

Instead of the 1,2-ethanediylbis (oxy) protecting group on the oxygen atom of carbon atom 17 there are also other keto protective groups in compound 5, such as, for example, the 2,2-dimethyl 1,3-propanediylbis (oxy) group suitable according to the invention.  

Variant IV:

R = methyl, ethyl;

In addition to ethanol, there are other alcohols, such as methanol or propanol, for which selective protection of the 3-carbonyl group in the form of the enol ether can be used according to the invention.

The further processing of the interconnections of the general Formulas IIa and IIb for the gestagen-active compounds of the general formula I can as described below in the general experimental section:  

According to Scheme 1, this is the case, for example, in European patent applications 0 110 434 and 0 127 864 described epoxy 1, in which R¹³ represents a methyl or ethyl group and K for a ketal protective group, converted into the vinyl estrone derivative 2 in several steps (E. Napolitano, R. Fiaschi and R.N. Hanson, Gaz. Chim. Ital. 120, 323 (1990)). Protection of The carbonyl function of 2 to the ketal 3 is achieved, for example, by reaction with ethylene glycol in dichloromethane and ortho-esters in the presence of p-toluenesulfonic acid [see for Example A.J. v.d. Broek, A.I.A. Broess, M.J. v.d. Heuvel, H.P. de Jongh, J. Leemhuis, K.H. Schönemann, J. Smits, J. de Visser, N.P. van Vliet and F.J. Zeelen, Steroids 30, 481 (1977)]. The 11β-vinyl compound 3 can be converted into the hydroxyethyl compound 4 for example by hydroboration with borane-dimethyl sulfide complex or 9-bora bicyclo [3.3.1] nonane in tetrahydrofuran and subsequent oxidation with hydrogen super oxide / sodium hydroxide [see for example Z. Paryzek and K. Blasczyk, Can. J. Chem. 65, 229 (1987); E.J. Corey and D.-C. Ha, Tetrahedron Lett. 29, 3171 (1988)]. The alcohol 4 can using methods known from the literature, such as, for example, by reaction with tetrabromomethane / Convert triphenylphosphine to the corresponding bromide 5 [see for example E.J. Corey and D.-C. Ha, Tetrahedron Lett. 29, 3171 (1988)]. In a base induced intramolecular cyclization, the spirodienone 6 is obtained from the bromide 5 [see for Example C. Iwato, T. Tanaka, T.Fusaka and N. Maezaki, Chem. Pharm. Bull. 32, 447 (1984); D. Hobbs-Mallyon and D.A. Whiting, J. Chem. Soc. Perkin I, 2277 (1991)]. The next step is optionally the selective hydrogenation of the 1,2-double bond of dienone 6 to enone 7. It is achieved by homogeneous catalytic hydrogenation on tris (triphenylphosphine) rhodium (I) chloride in a mixture of methanol or ethanol with benzene or toluene [see for Example C. Djerassi and J. Gutzwiller, J. Am. Chem. Soc. 88, 4537 (1966); K. Atsumi, T. Yokoshima, S. Ohyabu and N. Fukasaku, J. Labeled Compd. Rad. 23, 1005 (1986)].

Compounds 6 or 7 can be protected in the 3-protected according to methods known from the literature 17-Ketone 11 can be transferred: For example, 7 becomes that after acidic ketal splitting Endion 8 obtained, its selective reduction with sodium borohydride in solvents such as Example dichloromethane or tetrahydrofuran in a mixture with lower aliphatic alcohol get, preferably methanol, at temperatures between -78 and -30 ° C compound 9 results [see, for example, K. Atsumi, T. Yokoshima, S. Ohyabu and N. Fukasaku, J. Labeled Compd. Rad. 23: 1005 (1986); D.E. Ward, C.K. Rhee and W.M. Zoghaib, Tetrahedron Lett. 29, 517 (1988)]. According to known methods, compound 9 is transferred into ketal 10 and then oxidized to ketone 11 in the usual way. Compound 11 can be found in a similar sequence represent from the Dienon 6. To do this, the steroid 6 is treated with acid in the Diendione 12 converted, reduced to 17-hydroxysteroid 13 by the above-mentioned method and then, also as mentioned above, the 1,2-double bond is hydrogenated, compound 9 is obtained.  

Compound 11 can also be obtained by compound 5 using acidic ketal cleavage converted into ketone 14, then with complex hydrides, preferably Sodium borohydride (see above) reduced to the 17β-hydroxysteroid 15 and this - as above for Compound 5 described - base-induced cyclized to steroid 13, from which via 9 and 10 17-ketone 11 is accessible.

Furthermore, the selective protection of the 3-carbonyl group of the endion 8 by reaction with orthoesters, the corresponding alcohols and p-toluenesulfonic acid to give the corresponding Δ ^3,5 -dien-3-ols such as compound 16 is possible [see, for example, CW Marshall, JW Ralls , FJ Saunders and B. Riegel, J. Biol. Chem. 228, 339 (1957)].

The compounds 6, 7, 8, 11 and 12 are the starting products in the representation of Compounds of the general formula I.

The next steps then possibly include functionalizations in the D-ring. The Introduction of a 15.16 double bond (R¹⁵ and R¹⁶ form a common additional Binding) takes place, for example, by a modified Saegusa oxidation (I. Minami, K. Takahashi, I. Shimizu, T. Kimura and J. Tsuji, Tetrahedron 42, 2971 (1986); EP-A 0299913) of the corresponding enol compounds of ketone 11. If necessary, the double bond isomerized according to position 14. To this end, the 15,16-ene compounds are treated with Silica Gel / Triethylamine [p. Scholz, R. Hofmeister, G. Neef, E. Ottow, C. Scheidges and R. Wiechert, Liebigs Ann. Chem. 151 (1989)].

For examples in which R¹⁵ and R¹⁶ represent a common β-methylene group, this methylene group is introduced, for example, by implementing the corresponding corresponding Δ¹⁵-17-ketones with dimethylsulfoxonium methylide [see, for example, Germans Auslegeschrift 1183500, German Offenlegungsschrift 2922500, EP-A 19690, USP 4291029, E.J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 84, 867 (1962)].

After the D-ring modification has been carried out, the further steps initially apply to the introduction of the radicals R¹⁷ ^α and R¹⁷ ^β on the C-17 atom. This introduction is carried out analogously to methods known from the literature [for example J. Fried, JA Edwards, "Organic Reactions in Steroid Chemistry", van Nostrand Reinhold Company, 1972, Vol. 1 and 2; "Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, Vol 1-2) by nucleophilic addition to the C-17 ketone.

In the case of easily enolizable 17-ketones, such as the 14,15-ene compounds, if necessary, nucleophiles are introduced with the addition of cerium salts. [T. Imamoto, N. Takiyana, K. Nakamura and Y. Sugiura, Tetrahedron Lett. 25, 4233 (1984)].

The introduction of the substituent C≡CY as R¹⁷ ^α with the meanings given for Y is carried out with the aid of the metalated compounds, which can also be formed in situ and reacted with the 17-ketone. The metalated compounds are formed, for example, by reacting the acetylenes with alkali metals, in particular potassium, sodium or lithium, in the presence of an alcohol or in the presence of ammonia. The alkali metal can also act in the form of, for example, methyl or butyllithium.

3-Hydroxy-1-propyne in the 17-position is introduced by reacting the 17-ketone with the dianion of propargyl alcohol (3-hydroxypropine), for example with that in situ generated dipotassium salt of propargyl alcohol or with corresponding, at the hydroxy function-protected derivatives, such as the lithium compound of 3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-propyne.

The hydroxypropyl compounds can be prepared from the hydroxypropinyl derivatives become. The hydroxypropyl chain is represented, for example, by hydrogenation Room temperature and normal pressure in solvents such as methanol, ethanol, tetrahydrofuran or ethyl acetate with the addition of precious metal catalysts such as platinum or palladium.

The introduction of the hydroxyalkanes can also be carried out directly by reacting the 17-ketone with metalated derivatives are made [E.J. Corey and R.H. Wollenberg, J. Org. Chem. 40, 2265 (1975); H.P. On, W. Lewis and G. Doubt, Synthesis 999 (1981); G. Gohiez, A. Alexakis and J.F. Normant, Tetrahedron Lett. 3013 (1978); P.E. Eaton, G.F. Cooper, R.C. Johnson and R.H. Mueller, J. Org. Chem. 37, 1947 (1972)].

The introduction of branched and homologous hydroxyalkyne and hydroxyalkane groups is also in a corresponding manner possible.

17α-1,2-alkdienyl-substituted steroids are optional, for example, by reacting the THP ether, α-alkoxyethyl ether, alkyl or aryl sulfonates protected 1 7α- (3-hydroxy-1- alkyne-substituted compounds with complex hydrides in aliphatic or alicyclic Ethers [see for example A. Burger, J.-P. Roussel, C. Hetru, J.A. Hoffmann and B. Luu, Tetrahedron 45, 155 (1989); A. Claesson, L.-I. Olsson and C. Bogentoft, Acta Chem. Scand. 27, 2941 (1973); L.-I. Olsson and A. Claesson, Acta Chem. Scand. B31,614 (1977)] but also after  other methods known from the literature [see, for example, German Auslegeschrift 19 58 533; German Offenlegungsschrift 16 68 679] accessible.

The 17-cyanomethyl side chain is either built up directly from the 17-ketone Addition of acetonitrile or by cleaving the spiroepoxide with HCN, for example according to K. Ponsold, M. Hübner, H. Wagner and W. Schade, Z. Chem. 18, 259 (1978).

Products in which R¹⁷ ^α / R¹⁷ ^β for

with x = 1 or 2, for example from the 17α- (3-hydroxypropyl) - or 17α- (3-hydroxybutyl) compounds by oxidation with the Jones reagent, Braunstein, Pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine or the fetizone Represent reagent.

The synthesis of 16,17-α-methylene-17β-alkanoyl-substituted compounds follows methods known from the literature. For example, starting from the 17-ketones Δ¹⁶-17-perfluorosulfonyloxy compounds represent in the presence of transition metal catalysts can be coupled with alkoxyvinyltin or zinc compounds [see for example M. Kosugi, T. Sumiya, Y. Obara, M. Suzuki, H. Sano and T. Migita, Bull. Chem. Soc. Jpn. 60: 767 (1987); P.G. Ciattini, E. Morera and G. Ortar, Tetrahedron Lett. 31, 1889 (1990)]. Acid hydrolysis of the coupling products gives the Δ¹⁶-17-acetyl compounds. These enones can be used according to the above for the cyclopropanation of the Δ¹⁵-17 ketones specified process with trimethylsulfoxonium iodide to 16,17-α-methylene-17β-acetyl- Implement connections.

Compounds in which R¹⁷ ^{α is} an alkyl radical and R¹⁷ ^{β is} an alkanoyl radical can be prepared, for example, from Δ¹⁶-17-alkanoyl compounds or 17α-hydroxy-17β-alkanoyl compounds by reaction with lithium in liquid ammonia mixed with tetrahydrofuran 17- Enolate anions are generated which can be alkylated with alkyl halides to the desired compounds [see for example MJ Weiss, RE Schaub, GR Allen, Jr., JF Poletto, C. Pidacks, RB Conrow and CJ Coscia, Tetrahedron 20, 357 (1964)] .

The introduction of a hydroxyprogesterone chain (R¹⁷ ^β = acetyl, R¹⁷ ^a = hydroxy) takes place according to methods known from the literature.

Of particular note here is the route via a 17β-cyano-17α-hydroxy compound [Cyanohydrin method; see u. a. DE 39 31 064 A1 (1989); GDR patient 147669 (1981); DE 21 10 140 (1971); Yep Pat. No. 57062296-300 (1982); J.C. Gase and L. Nedelec, Tetrahedron Lett. 2005 (1971), J.N.M. Batiste, N.C.M.E. Barendse and A.F. Marx, Steroids 55, 109 (1990)].

Here, the 17-ketone is reacted with, for example, acetone cyanohydrin Solvent systems, for example ethanol or methanol and dichloromethane in one suitable (mostly slightly basic) pH value (is determined by adding KCN or NaCN or KOH or NaOH adjusted) implemented. Under these reaction conditions, a Crystallization of the 17β-cyano compound can be achieved. The 17α-hydroxy function will then protected, and then the cyano group is left with, for example, methyl lithium or methyl magnesium halides react and then, after acidic cleavage, to give the hydroxy progesterone chain to arrive. By reacting the above protected cyanohydrins with others Alkyl lithium or alkyl magnesium compounds and subsequent acidic cleavage can homologous 17α-hydroxy-17β-alkanoyl compounds can be obtained.

Starting from the 17α-hydroxy-17β-alkanoyl compounds can then in a known manner the 17α-alkanoyloxy derivatives are obtained.

The transfer of 17α-ethynyl-17β-nitrooxy- Compounds [see H. Hofmeister, K. Annen, H. Laurent and R. Wiechert, Chem. Ber. 111, 3086 (1978)] or from 17α-ethynyl-17β-hydroxy compounds by reaction with Phenylsulfenyl chloride generated allene sulfoxides [see V. VanRheenen and K.P. Shephard, J. Org. Chem. 44, 1582 (1979)] into the 17α-hydroxy-17β-acetyl compounds.

The next steps usually apply to the structure of the radicals R⁶, R ^{6 '} , R⁷ and R¹ and R².

For end connections in which, in addition to the 4.5, also a 1,2 and / or a 6.7 double bond is present or for corresponding intermediates in which all double bonds coexist other are desired, starting from the Δ⁴-3-ketone via a 2,6-dibromination and subsequent elimination both double bonds are introduced simultaneously [see for example German Auslegeschrift 1119266).  

However, it is often necessary, due to the different functionalities in the molecule, the two Introduce double bonds one after the other. As a rule, the first step is the introduction a 6.7 double bond instead. This introduction is achieved using dienol ether bromination and subsequent elimination of hydrogen bromide [see, for example, J. Fried, J.A. Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, pp. 265-374] or also by reaction with chloranil or 2,3-dichloro-5,6-dicyanobenzoquinone.

Dienol ether bromination can, for example, analogously to the instructions in Steroids 1, 233 (1965) respectively. The hydrogen bromide is eliminated by heating the 6-bromo compound basic agents, such as lithium bromide or lithium carbonate in aprotic Solvents such as dimethylformamide at temperatures of 50-120 ° C or by the 6-bromo compounds are heated in collidine or lutidine.

Depending on the desired end connection, the introduction of a 1,2-double bond can be carried out directly after Introduction of the 6.7 double bond or at a later intermediate stage. These Dehydration is preferably accomplished by chemical or microbiological means in principle methods known from the literature [see for example DE 34 02 329 A1 and EP-A 150157].

Chemical dehydration takes place, for example, by heating with selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranil, thallium triacetate or lead tetraacetate in suitable solvents such as dioxane, tert. Butanol, tetrahydrofuran, toluene, Benzene or mixtures of these solvents.

The introduction of the 1,2-double bond can also be done by a modified Saegusa-Oxi dation [I. Minami, K. Takahashi, I. Shimizu, T. Kimura and J. Tsuji, Tetrahedron 42, 2971 (1986); EP-A 0299913] of the corresponding enol compounds of 3-ketone.

Compounds that have a 1,2α-methylene function are made from the 1,2-unsaturated Compounds by reaction with dimethylsulfoxonium methylide analogous to the representation of the 15,16β-methylene compounds (see above). Here is a selective introduction of 1,2-methylene function also possible in the presence of the 4,6-diene-3-one unit [see for Example German interpretation 1183500].

For compounds with a 6,7-methylene function, the introduction also follows from the Dienone by reaction with dimethylsulfoxonium methylide, although here a mixture the α and β isomers occur (the ratio depends on the substrates used and is approximately 1: 1), which can be separated, for example, by column chromatography.  

Compounds with R⁷ equal to alkyl are made from the 4,6-diene-3-one compounds 1,6-addition prepared by known methods [J. Fried, J.A. Edwards: "Organic Reactions in Steroid Chemistry ", by Nostrand Reinhold Company 1972, pages 75 to 82; A. Hosomi and H. Sakurai, J. Am. Chem. Soc. 99, 1673 (1977)]. The introduction of the 7-alkyl functions usually takes place via the dialkyl copper lithium compounds.

Compounds in which R⁶ represents a chlorine atom and R ^{6 '} and R⁷ form a common additional bond are also prepared starting from the 4,6-diene-3-one compounds. For this purpose, the 6,7-double bond is first epoxidized using organic peracids, such as, for example, meta-chloroperbenzoic acid in methylene chloride, optionally in the presence of sodium hydrogen carbonate solution [see W. Adam, J.-C. Liu and O. Rodriguez, J. Org. Chem. 38, 2269 (1973)]. This epoxide is opened and the primarily formed 7α-hydroxy group is eliminated, for example, by reaction with hydrogen chloride gas in glacial acetic acid [see, inter alia, DE-AS 11 58 966 and DE 40 06 165 A1].

The introduction of a 6-methylene group can, for example, start from a 3-amino 3,5-diene derivative by reaction with formalin in alcoholic solutions to form a 6α-hydroxymethyl group and subsequent acidic elimination of water, for example with Hydrochloric acid in dioxane / water. The elimination of water can also be done in this way take place that an escape group is first introduced and then eliminated. As an escape Groups such as mesylate, tosylate or benzoate are suitable [see DE 34 02 329 A1, EP-A 150157, US 4,584,288 (86); K. Nickisch, S. Beier, D. Bittler, W. Elger, H. Laurent, W. Losert, Y. Nishino, E. Schillinger and R. Wiechert, J. Med. Chem. 34, 2464 (1991)].

Another option for introducing the 6-methylene compounds is direct Reaction of the 4 (5) unsaturated 3-ketones with acetals of formaldehyde in the presence of Sodium acetate with, for example, phosphorus oxychloride or phosphorus pentachloride in suitable Solvents such as chloroform [see for example K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34, (1982)].

The 6-methylene compounds can be used to prepare compounds of the general formula I in which R⁶ is methyl and R ^{6 '} and R⁷ form a common additional bond.

For example, one of D. Burn, D.N. Kirk and V. Petrov in Tetrahedron Use 21.1619 (1965) described method in which an isomerization of the double binding by heating the 6-methylene compounds in ethanol with 5% palladium-carbon as Catalyst, either with hydrogen or by heating with a small amount Cyclohexene has been pretreated. The isomerization cannot even with one pretreated catalyst take place when a small amount is added to the reaction mixture Cyclohexene is added. The occurrence of small amounts of hydrogenated products can be caused by Addition of an excess of sodium acetate can be prevented.

However, 6-methyl-4,6-dien-3-one derivatives can also be prepared directly [see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Liebigs Ann. Chem. 712, (1983)].

Compounds in which R⁶ represents an α-methyl function can from the 6-methylene Compounds can be prepared by hydrogenation under suitable conditions. The best Results (selective hydrogenation of the exo-methylene function) are obtained by transfer hydrogenation reached [E.A. Brande, R.P. Linstead and P.W.D. Mitchell, J. Chem. Soc. 3578 (1954)]. Heated the 6-methylene derivatives in a suitable solvent, such as ethanol, in The presence of a hydride donor, such as cyclo-hexene, is very good Yields to 6α-methyl derivatives. Small amounts of 6β-methyl compounds can be acidic can be isomerized [see, for example, D. Burn, D.N. Kirk and V. Petrov, Tetrahedron 21, 1619 (1965)].

The targeted representation of 6β-alkyl compounds is also possible. For this, the 4 (5) unsaturated 3-ketones for example with ethylene glycol and trimethyl orthoformate in Dichloromethane in the presence of catalytic amounts of an acid (e.g. p-toluene Sulfonic acid) to the corresponding 3-ketals. During this ketalization the double bond isomerizes to position 5 (6). A selective epoxidation of this 5 (6) double bond can be achieved, for example, by using organic peracids in suitable solvents such as dichloromethane. Alternatively, epoxidation can also be used with hydrogen peroxide in the presence of, for example, hexachloroacetone or 3-nitrotri fluoracetophenone. The 5,6α-epoxides formed can then be prepared using for example, alkyl magnesium halides or alkyl lithium compounds opened axially become. This leads to 5α-hydroxy-6β-alkyl compounds. The split of the 3-keto protecting group can be added under mild acidic conditions (acetic acid or 4N hydrochloric acid 0 ° C) while maintaining the 5α-hydroxy function. Basic elimination of the 5α-hydroxy Function, for example with dilute aqueous sodium hydroxide solution, gives the 3-keto-4-ene verbin with a 6-alkyl group in the β position. Alternatively, the ketal cleavage results in  more drastic conditions (aqueous hydrochloric acid or another strong acid) that correspond corresponding 6α-alkyl compounds.

After all residues have been introduced, existing protective groups are replaced using standard procedures cleaved.

The compounds of general formula I obtained with R³ = oxygen can if desired by reaction with hydroxylamine hydrochloride in the presence of tert.- Amines are converted into oximes at temperatures between -20 and + 40 ° C (general Formula I with R³ in the meaning of N-OH, the hydroxyl group syn- or anti-standing can be).

The removal of the 3-oxo group to an end product of the general formula I with R³ in the The meaning of two hydrogen atoms can, for example, according to that in DE-A-28 05 490 specified rule by reductive cleavage of the thioketal.

The following examples serve to explain the invention in more detail:  

example 1 17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one a) 3- (Acetyloxy) -17.17- [1,2-ethanediylbis (oxy)] - 11β-ethenylestra-1,3,5 (10) -triene [3]

Under an argon atmosphere, 440 ml of ethylene glycol are added to a solution of 12.3 g of 3- (acetyloxy) -11β-ethenylestra-1,3,5 (10) -trien-17-one [2] in 120 ml of dichloromethane with vigorous stirring , 12 ml of trimethyl orthoformate and 100 mg of p-toluenesulfonic acid and stirred vigorously for 48 hours. Then poured onto 1 l of saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The extracts are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. 13.8 g of 1a) are obtained as a pale yellow resin.
[α] _D ²⁰ = + 31.8 ° (CHCl₃; c = 0.50).
1 H-NMR (CDCl₃): δ = 7.10 ppm d (J = 7.5 Hz, 1H, H-1); 6.80 dd (J = 7.5, 2 Hz, 1H, H-2); 6.78 s (broad) (1H, H-4); 5.73 ddd (J = 15, 10, 7.5 Hz, 1H, ethenyl-H); 5.03 ddd (J = 15, 1.1 Hz, 1H, ethenyl-H); 4.95 ddd (J = 10, 1.1 Hz, 1H, ethenyl-H); 3.88-4.00 m (4H, ketal); 2.28 s (3H, CH₃); 0.93 s (3H, CH₃)

b) 17,17- [1,2-ethanediylbis (oxy)] - 11β- (2-hydroxyethyl) estra-1,3,5 (10) -trien-3-ol [4]

220 ml of a 0.5 molar solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran are added dropwise to a solution of 13 g of the substance described in 1a) in 175 ml of tetrahydrofuran at 20 ° C. under an argon atmosphere within 15 minutes and then stirred for 4 hours . With cooling in an ice bath, 130 ml of 2.5 normal sodium hydroxide solution and 75 ml of 30% hydrogen peroxide solution are then added dropwise in succession. When the dropwise addition is complete, the mixture is stirred at 70 ° C. for 2 hours. The cooled reaction mixture is then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed successively with saturated aqueous sodium thiosulfate solution and sodium chloride solution, dried over sodium sulfate and filtered. At 40 ° C is concentrated in vacuo to about 100 ml. The precipitated white crystals are filtered off and washed with cold ethyl acetate. 7.48 g 1b) are obtained. Column chromatography of the mother liquor on silica gel with a mixture of ethyl acetate and n-hexane gives a further 2.46 g 1b).
Mp = 223-232 ° C; [α] _D ²⁰ = +102.3 (CH₃OH; c = 0.505).
1 H-NMR (D₆-DMSO): δ = 8.92 ppm s (broad) (1H, OH); 6.95 d (J = 7.5 Hz, 1H, H-1); 6.55 dd (J = 7.5, 2 Hz, 1H, H-2); 6.42 m (1H, H -4); 4.20 t (J = 6 Hz, 2H, CH₂O); 3.78-3.90 m (4H, ketal); 0.96 s (3H, CH₃)

c) 11β- (2-bromoethyl) -17.17- [1,2-ethanediylbis (oxy)] estra-1,3,5 (10) -trien-3-ol [5]

Under an argon atmosphere, 100 ml of pyridine are added to a suspension of 9.9 g of the compound described in 1b) in 1.3 l of dichloromethane and the mixture is stirred until a clear solution is formed. 7.9 g of triphenylphosphine and 11.8 g of tetrabromomethane are added to this solution and the mixture is stirred for 1 hour. A further 7.9 g of triphenylphosphine and 11.8 g of tetrabromomethane are then added and the mixture is stirred for 1.5 hours. The reaction mixture is concentrated in vacuo at 30 ° C. and the residue is chromatographed on silica gel with a mixture of ethyl acetate and n-hexane. 9.98 g 1c) are obtained.
Mp = 185-188 ° C; [α] _D ²⁰ = + 63.6 ° (CHCl₃; c = 0.495).
1 H-NMR (CDCl₃): δ = 7.06 d (J = 7.5 Hz, 1H, H-1); 6.67 dd (J = 7.5, 2 Hz, 1H, H-2); 6.54 d (J = 2 Hz, 1H, H-4); 4.71 s (1H, OH); 3.88-4.00 m (4H, ketal); 3.38-3.60 m (2H, CH₂Br); 1.00 s (3H, CH₃)

d) 17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-1,4-diene 3-on [6]

Under an argon atmosphere, 9.9 g of the compound described under 1c) are dissolved in 550 ml of tert-butanol while heating to 50 ° C., 3.15 g of potassium tert-butoxide are added to the clear solution and the mixture is stirred at 50 ° C. for 1 hour . The cooled reaction mixture is poured onto ethyl acetate, washed with water and the aqueous phase extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed in vacuo. Column chromatography of the crude product on silica gel with a mixture of ethyl acetate and n-hexane gives 7.3 g 1d).
Mp = 163-167 ° C; [α] _D ²⁰ = 0.6 ° (CDCl₃; c = 0.50).
1 H-NMR (CDCl₃): δ = 7.08 ppm d (J = 10 Hz, 1-H, H-1); 6.19 dd (J = 10, 1 Hz, 1H, H-2); 6.16 s (broad) (1H, H-4); 3.80-3.97 m (4H, ketal); 1.09 s (3H, CH₃)

e) 17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en- 3-on [7]

1.89 g of tris (triphenylphosphine) rhodium (I) chloride are added to a solution of 6.95 g of the compound described in 1d) in 570 ml of toluene and 160 ml of ethanol, the apparatus is rinsed with hydrogen and then stirred for 5 hours under a Hydrogen atmosphere. A weak stream of argon is then passed through the solution for 5 minutes; then the solvent is distilled off in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate and n-hexane. 6.72 g of 1e) are obtained as a pale brown solid.
Mp = 152-154 ° C; [α] _D ²⁰ = + 98.5 ° (CDCl₃; c = 0.535).
1 H-NMR (CDCl₃): δ = 5.80 ppm s (broad) (1H, H-4); 3.80-3.98 m (4H, ketal); 1.06 s (3H, CH₃).

f) 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3,17-dione [8]

4 ml of four normal aqueous hydrochloric acid are added dropwise to a solution of 6.7 g of the compound described under 1e) in 250 ml of acetone, the mixture is stirred for 30 minutes at room temperature, then poured onto two-molar aqueous sodium carbonate solution and extracted twice with ethyl acetate. After drying the combined organic phases over sodium sulfate, the mixture is filtered and the solvent is distilled off in vacuo. 5.84 g 1f) are obtained as a light brown resin which crystallizes from diisopropyl ether.
F _p = 118-120 ° C; [α] _D ²⁰ = + 201.6 ° (CHCl₃; c = 0.535).
1 H-NMR (CDCl₃): δ = 5.82 ppm s (broad) (1H, H-4); 1.08 s (3H, CH₃).

g) 3-Ethoxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-3,5-dien-17-one

To a solution of 5.8 g of the compound described under 1f) in 200 ml of dichloromethane there are 1.25 ml of ethanol, 19.5 ml of triethyl orthoformate and then at 0 ° C 25 mg of p-toluene sulfonic acid. The reaction mixture is stirred at 0 ° C for 5 hours. To the deep purple Solution are then 5 ml of pyridine and after 5 minutes 100 ml of saturated aqueous sodium added hydrogen carbonate solution. The phases are separated; the aqueous phase is with Extracted dichloromethane and the combined organic phases once with water washed. After drying over sodium sulfate, the mixture is filtered and the solvent in Vacuum distilled off. 7.1 g of 1 g) are obtained as a light brown resin which is immediately reacted further becomes.

h) 17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one

700 ml of absolute tetrahydrofuran are saturated with Ethingas at 0 ° C for 30 minutes. 100 ml of a 1.6 molar solution of n-butyllithium in n-hexane are then added under argon and the mixture is stirred at 0 ° C. for a further 30 minutes. A solution of 7.1 g of the substance described under 1 g) in 100 ml of absolute tetrahydrofuran is then added dropwise within 30 minutes. The mixture is stirred for 2 hours at 0 ° C and then mixed with 50 ml of water. 100 ml of six normal hydrochloric acid are then added dropwise and the mixture is stirred vigorously at room temperature for 3 hours. The reaction mixture is diluted with water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and the solvent is distilled off in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane. 3.78 g 1h) are obtained as a white solid.
Mp = 208-211 ° C; [α] _D ²⁰ = + 73.0 ° (CHCl₃; c = 0.515).

Example 2 17β-Hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one

100 ml of absolute tetrahydrofuran are saturated with propyne gas at 0 ° C for 30 minutes. 15 ml of a 1.6 molar solution of n-butyllithium in n-hexane are then added under argon and the mixture is stirred at 0 ° C. for a further 30 minutes. A solution of 0.82 g of the substance described under 1 g) in 20 ml of absolute tetrahydrofuran is then added dropwise within 15 minutes. The mixture is stirred at 0 ° C. for 1 hour and then quenched with 50 ml of water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are concentrated in vacuo, taken up in 20 ml of tetrahydrofuran, 5 ml of five normal aqueous hydrochloric acids are added and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured onto water and extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and the solvent is distilled off in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane. 0.46 g 2) is obtained as a white solid.
Mp = 218-222 ° C; [α] _D ²⁰ = + 63.6 ° (CHCl₃; c = 0.511).
1 H-NMR (CDCl₃): δ = 5.81 ppm s (broad) (1H, H-4); 1.89 s (3H, propyne CH₃); 1.05 s (3H, CH₃).

Example 3 17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-en-3.20-dione a) [17 (21) S, 21 (R)] - [17 (21) S, 21 (S)] - 21- (phenylsulfinyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclo penta [10,9,11] -19-norpregn-4,17 (20), 20-trien-3-one

A solution of 275 mg of phenyl sulfenyl chloride in 0.7 ml of dichloromethane is added dropwise at -70 ° C. under argon to a solution of 0.36 g of the compound described under 1h) in 7 ml of dichloromethane and 1 ml of triethylamine. Then allowed to warm to -40 C and stir for 2.4 hours at this temperature. The reaction mixture is then quenched with water and extracted with dichloromethane. The organic phase is washed successively with normal aqueous hydrochloric acid and water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane. 0.46 g 3a) is obtained as a white solid.
1 H-NMR (CDCl₃): δ = 7.60-7.68 ppm m (2H, aromatic); 7.45-7.57 m (3H, aromatics); 6.15 (6.12) t (J = 3.5 Hz, 1H, Allen); 5.81 s (broad) (1H, H-4); 1.06 (1.12) s (3H, CH₃) (signals of the epimeric sulphoxide in brackets).

b) 17-Hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-en-3,20-dione

To a solution of 0.44 g of the compound described in 3a) in 5 ml of tetrahydrofuran is added dropwise at room temperature under argon 4 ml of a one molar solution of sodium methylate in methanol and stirred for 3 hours at room temperature. Then it is poured onto water, extracted four times with dichloromethane, the combined organic phases are washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The remaining residue is suspended in 10 ml of methanol, 2 ml of triethyl phosphite and refluxed for 30 minutes. After cooling, 10 ml of acetone and 2 ml of two-normal aqueous hydrochloric acid are added, the mixture is stirred at room temperature for 15 minutes and then concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane. 168 mg 3b) are obtained as a pale yellow solid.
Mp = 248-255 ° C; [α] _D ²⁰ = + 115.8 ° (CHCl₃; c = 0.500).
1 H-NMR (CDCl₃): δ = 5.81 ppm s (broad) (1H, H-4); 2.27 s (3H, CH₃); 0.89 s (3H, CH₃).

c) 17- (Acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-en-3,20-dione

160 mg of the compound described under 3b) are suspended in 4 ml of acetic acid and 1 ml of trifluoroacetic anhydride is added dropwise at 10 ° C. with stirring. After 2 hours of stirring at room temperature and after a further hour of stirring, 0.5 ml of trifluoroacetic anhydride are again added. After stirring for a total of 4 hours, the mixture is concentrated in vacuo at room temperature, the remaining residue is taken up in dichloromethane, extracted with saturated aqueous sodium bicarbonate solution, the organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The remaining crude product is purified by column chromatography on aluminum oxide of activity level III with a mixture of ethyl acetate and n-hexane. 72 mg 3c) are obtained as a white solid.
Mp = 196-200 ° C; [α] _D ²⁰ = + 103.7 ° (CHCl₃; c = 0.505).
1 H-NMR (CDCl₃): δ = 5.82 ppm s (broad) (1H, H-4); 2.12 s (3H, CH₃); 2.05 s (3H, CH₃); 0.80 s (3H, CH₃).

Example 4 17- (Acetyloxy) -4 ′, 5 ′, 9.11α-tetrahydrocyclopenta [10.9.11] -19-norpregna-4,6-diene-3.20dione

100 mg of the compound described under 3c) are suspended in 8 ml of tert-butanol, 175 mg of chloranil are added and the mixture is refluxed for 4 hours under an argon atmosphere. After cooling, the mixture is diluted with dichloromethane, washed with water, twice with 1N sodium hydroxide solution and again with water, the organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The remaining crude product is purified by column chromatography on silica gel with a mixture of acetone and n-hexane. 29 mg 4) are obtained as a light brown solid.
Mp = 229-233 ° C.
1 H-NMR (CDCl₃): δ = 6.18 ppm s (broad) (2H, H-6 and H-7); 5.73 s (broad) (1H, 4-H); 2.09 s (3H, CH₃); 2.02 s (3H, CH₃); 0.80 s (3H, CH₃).

Example 5 17- (acetyloxy) -6-methylene-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10.9.11] -19-norpregn- 4-en-3.20-dione

0.82 ml of triethyl orthoformate, 0.82 ml of ethanol and 20 mg of p-toluenesulfonic acid are added to a solution of 315 mg of the compound described in 3c) in 8 ml of tetrahydrofuran under an argon atmosphere, and the mixture is stirred at 40 ° C. for 30 minutes. Then 0.25 ml of N-methylaniline and 0.28 ml of 37% aqueous formalin solution are added at room temperature and the mixture is stirred at 40 ° C. for 1 hour. Again at room temperature, 0.8 ml of 6N hydrochloric acid is added, the mixture is stirred for 3 hours, poured onto saturated sodium chloride solution, extracted twice with ethyl acetate, the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo . The crude product obtained is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane. 111 mg 5) are obtained as a pale yellow solid.
Mp = 171-173 ° C; [α] _D ²⁰ = + 208.4 ° (CHCl₃; c = 0.495).
1 H-NMR (CDCl₃): δ = 6.02 ppm s (broad) (1H, H-4); 5.22 m (1H, ex-methylene); 4.99 m (1H, ex-methylene); 2.14 s (3H, CH3); 2.05 s (3H, CH₃); 0.78 s (3H, CH₃).

Claims (7)

1. 10,11β-C₂-bridged steroids of the general formula I wherein
R¹ and R² each for a hydrogen atom, together for an additional bond or together for an α-methylene group,
R³ for one oxygen atom, the hydroxyimino group or two hydrogen atoms,
R⁶ for a hydrogen, fluorine, chlorine or bromine atom or for an α- or β-C₁-C₄-alkyl radical when R ^{6 '} and R⁷ represent hydrogen atoms, or else
R⁶ for a hydrogen, fluorine, chlorine or bromine atom or for a C₁-C₄-alkyl radical if R⁶ ^′ and R⁷ together represent an additional bond,
R⁷ for an α or C₁-C₄ alkyl radical when R⁶ and R⁶ ^' represent hydrogen atoms, or else
R⁶ and R⁷ together for an α- or β-methylene group and R ^{6 '} for a hydrogen atom or
R⁶ and R ^{6 ′} together for an ethylene group or methylene group and R⁷ for a hydrogen atom,
R¹³ represents a methyl or ethyl group,
R¹⁴, R¹⁵ and R¹⁶ each represent a hydrogen atom or
R¹⁴ for a hydrogen atom and R¹⁵ and R¹⁶ together for an additional bond or an α- or β-methylene group, or
R¹⁶ for a hydrogen atom and R¹⁴ and R¹⁵ together for an additional bond,
R¹⁷ ^β for a hydroxy, C₁-C₄ alkoxy or C₁-C₄ alkanoyloxy group and
R¹⁷ ^α for a hydrogen atom, for a radical - (CH₂) _n CH₂Z, where n = 0, 1, 2 or 3 and Z is a hydrogen atom, the cyano group, a radical CO₂R¹⁸ with R¹⁸ in the meaning of a C₁-C₄ alkyl group or a Radical OR¹⁹ with R¹⁹ is hydrogen, a C1-C4-alkyl or C1-C4-alkanoyl group
for a grouping - (CH₂) _m C≡CY, where m = 0, 1 or 2 and Y is a hydrogen atom, a C₁-C₄-alkyl or a C₁-C₄-hydroxyalkyl radical or a fluorine, chlorine, bromine or For a grouping, iodine atom is -CH = C = CR²⁰R²¹, where R²⁰ and R²¹ independently of one another represent a hydrogen atom or a C₁-C₄ alkyl group, or
R¹⁷ ^β for a C₁-C₄ alkanoyl group and R¹⁷ ^α for a hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkanoyloxy or C₁-C₄ alkyl group, or
R¹⁶ and R¹⁷ ^α together for an α-methylene group, or
R¹⁷ ^α and R¹⁷ ^β together for a radical of the formula with x = 1 or 2. 2. Compounds according to claim 1, wherein
R³ for one oxygen atom or two hydrogen atoms,
R⁶ and R ^{6 '} each for a hydrogen atom or for a three ring formed together with the carbon atom 6, or
R⁶ for a chlorine or bromine atom or for a straight-chain saturated α- or β-C₁-C₄-alkyl radical, or
R ^{6 '} and R⁷ together for a methylene bridge or together for an additional double bond, or
R⁷ represents a straight-chain or branched-chain saturated α- or β-alkyl radical having up to 4 carbon atoms,
R¹⁴, R¹⁵ and R¹⁶ each represent a hydrogen atom or
R¹⁴ represent an α-hydrogen atom and R¹⁵ and R¹⁶ together represent an additional bond or a β-methylene bridge, mean,
and the other substituents can all have the meanings given in formula I. 3. Compounds according to claim 1, namely
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-en-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-ene-3,20-dione;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregna-4,6-diene-3,20-ion;
17- (acetyloxy) -6α-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregn-4-ene-3,20-dione;
17- (acetyloxy) -6-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -19-norpregna-4,6-diene-3,20-ion;
17- (acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 19-norpregn-4-en-3 , 20-dione;
17- (acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 19-norpregna-4,6-diene -3,20-dione;
17- (acetyloxy) -6-methyl-1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclo propa [1,2] -19-norpregna- 4,6-diene-3,20-dione;
17- (Acetyloxy) -6-chloro-1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 19-norpregna-4 , 6-diene-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregn-4-ene-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo- 19-norpregn-4-en-3.20-dione;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo- 19-norpregn-4-en-3,20-dione;
17- (acetyloxy) -6-chloro-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-19-norpregna-4,6-diene-3,20-dione;
17- (Acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 18a-homo-19-norpregn-4 -en-3,20-dione;
17- (acetyloxy) -1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 18a-homo-19-norpregna-4 , 6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclopropa [1,2] - 18a-homo-19 -norpregna-4,6-diene-3,20-dione;
17- (Acetyloxy) -6-chloro-1β, 2β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] [3′′H] cyclo-propa [1,2] - 18a-homo -19-norpregna-4,6-diene-3,20-dione;
3 ′ ′, 16β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] cyclopropa [16,17] -19-norpregn- 4-en3,20-dione;
3 ′ ′, 16β, 4 ′, 5 ′, 9,11α-hexahydrocyclopenta [10,9,11] cyclopropa [16,17] -18a-homo- 19-nor-pregn-4-en-3,20-dione ;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one;
17β-hydroxy-17α- (propa-1,2-dienyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,1 1] estr-4-en- 3-one;
3 ′ ′, 4 ′ ′, 4 ′, 5 ′, 9,11α- [hexahydrocyclopent [10,9,11] estr-4-en-17β, 2 ′ ′ (5 ′ ′) - furan] -3,5 ′ ′ -Dion;
17α-ethynyl-17β-hydroxy-4 ^′ , 5 ^′ , 9,11α-tetrahydrocyclopental [10,9,11] -18a-homoestr-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo estr-4-en-3-one;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-4,15-dien-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] -estra-4,15-dien-3-one;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestra-4,15-dien-3-one;
17β-Hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestra- 4,15-dien-3-one. 4. Intermediate compounds of general formulas IIa and IIb for the preparation of the compounds of general formula I according to claim 1: wherein
A and B are each a hydrogen atom or together an additional bond, K¹⁷ is a free or protected in the form of a ketal keto oxygen atom, K³ is a keto protected in the form of a keto oxygen atom, and R is a methyl or ethyl group. 5. Interconnections according to claim 4, namely:
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-1,4-dien-3-one;
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3-one;
3,3- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-5-en-17-one;
4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estra-1,4-diene-3,17-dione;
4 ′, 5 ′, 9,11α-tetrahydrocyclopent [10,9,11] estr-4-en-3,17-dione;
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homo-estra -1,4-dien-3-one;
17,17- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestr -4-en-3-one;
3,3- [1,2-ethanediylbis (oxy)] - 4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestr -5-en-17-one;
4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestra-1,4-diene-3,17-dione;
4 ′, 5 ′, 9,11α-tetrahydrocyclopenta [10,9,11] -18a-homoestr-4-en-3,17-dione. 6. Pharmaceutical preparations containing at least one compound of the general Formula I according to claim 1 and a pharmaceutically acceptable carrier. 7. Use of the compounds of general formula I according to claim 1 for Manufacture of drugs.